EP2554546B1 - Gegen stoffwechselenzyme beständige pyripyropenderivate mit acat2-hemmender wirkung - Google Patents

Gegen stoffwechselenzyme beständige pyripyropenderivate mit acat2-hemmender wirkung Download PDF

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EP2554546B1
EP2554546B1 EP11762699.4A EP11762699A EP2554546B1 EP 2554546 B1 EP2554546 B1 EP 2554546B1 EP 11762699 A EP11762699 A EP 11762699A EP 2554546 B1 EP2554546 B1 EP 2554546B1
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EP2554546A1 (de
EP2554546A4 (de
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Hiroshi Tomoda
Tohru Nagamitsu
Daisuke Matsuda
Taichi Ohshiro
Masaki Ohtawa
Satoshi Omura
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Kitasato Institute
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Kitasato Institute
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • the present invention relates to pyripyropene A derivatives having an extremely good inhibitory activity against cholesterol acyltransferase isozyme 2 (hereinafter abbreviated as ACAT2). More particularly, the present invention relates to pyripyropene A derivatives in which the 1- and 11- positions are substituted by a cyclic acetal group.
  • ACAT2 cholesterol acyltransferase isozyme 2
  • the number of patients in Japan with hyperlipemia or arteriosclerosis which are associated with a high risk of high-mortality diseases such as myocardial infarction and cerebral apoplexy is said to be as many as thirty million, including subjects having no subjective symptoms. Even at the present time when the Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases have been revised by the Japan Atherosclerosis Society, death due to these diseases ranks high among the causes of death in Japan. Hyperlipemia and arteriosclerosis are significant health problems not only in Japan but also in Europe and the Americas.
  • statin drugs which specifically inhibit hydroxy-3-methylglutaryl coenzyme A (hereinafter abbreviated as HMG-CoA) reductase.
  • HMG-CoA hydroxy-3-methylglutaryl coenzyme A
  • Statin drugs have been the most widely sold drugs in the world for 8 consecutive years from 2001. They are widely used, as demonstrated by the fact that two statin drugs ranked in the top thirty drugs having the highest worldwide sales in 2008. However, in actuality, it has been found that these drugs exhibit an effect on prevention of onset in only 30% - 40% of patients and produce no suppression of cardiovascular diseases or the like in about half of patients who received therapy with such a drug (Non-Patent Document 1).
  • HMG-CoA reductase inhibitors which are currently used as prophylactic or therapeutic agents for arteriosclerosis cannot sufficiently suppress cardiovascular diseases or similar diseases are thought to relate to the fact that the mechanism of onset of arteriosclerosis is complicated, the onset mostly being caused by heredity, diabetes, drugs, and other various factors acting in combination. Therefore, diagnosis and treatment of these diseases need to be based on the pathological conditions of each patient.
  • ACAT Cholesterol acyltransferase
  • ACAT exists in the form of two isozymes, ACAT 1 and ACAT2, which have different in vivo functions and different locations from each other (Non-Patent Document 3).
  • ACAT1 is widely found in many living cells and tissues and is highly expressed particularly in macrofages and smooth muscle cells. It takes part in arteriosclerosis by causing the formation of foam macrophage cells, which are a cause of arteriosclerosis.
  • ACAT2 is expressed specifically in the small intestine and liver and is thought to take part in the absorption of dietary cholesterol and the secretion of very low-density lipoproteins in each of these organs. As the difference between ACAT1 and ACAT2 with respect to in vivo functions becomes clear, the importance of specifying its selectivity has been recognized in the development of new drugs targeted at ACAT.
  • Non-Patent Document 4 It has been found that synthetic ACAT inhibitors, the development of which has been abandoned, have an activity which selectively inhibits ACAT1 (such as Wu-V-23) or which inhibits both ACAT1 and ACAT2 (such as avasimibe and pactimibe) (Non-Patent Document 4).
  • Non-Patent Document 5 Taking the recently reported results of knockout mice (Non-Patent Document 5) into consideration, there is a strong expectation that a new drug will be developed from the family of selective ACAT2 inhibitors. It is reported that pyripyropene A having the formula shown below (Non-Patent Document 6) is a selective ACAT2 inhibitor (Non-Patent Document 7). However, up to the present time, there has been no research aimed at development of a new drug which is a selective ACAT2 inhibitor.
  • Patent Document 1 It is disclosed in Patent Document 1 that pyripyropene derivatives in which the 1-, 7- and/or 11-positions of pyripyropene A are substituted by certain groups have an ACAT2-inhibiting activity. However, it is not disclosed or suggested in that document that ACAT2 inhibition is achieved without decomposition by metabolizing enzymes.
  • Non-Patent Document 1 Libby, J. Am. Coll. Cardiol., vol 46, pp 1225-1228,2005
  • Non-Patent Document 2 Meuwese et al., Curr. Opin. Lipidol., Vol. 17, pp. 426-431, 2006 ;
  • Non-Patent Document 3 Chang et al., Acta. Biochim. Biophys. Sin., vol.
  • Non-Patent Document 4 Farese, Arterioscler. Thromb. Vasc. Biol., vol. 26, pp. 1684-1686, 2006 ;
  • Non-Patent Document 5 Bell et al., Arterioscler. Thromb. Vasc. Biol., vol. 27, pp. 1396-1402, 2007 ;
  • Non-Patent Document 6 Tomoda et al., J. Antibiot. Vol. 47, pp. 148-153, 1994 ;
  • Non-Patent Document 7 Lada et al., J. Lipid Res., vol. 45, pp. 378-386, 2004 ;
  • Patent Document 1 WO 2009/081957 .
  • Another object of the present invention is to provide a compound which is useful as an effective prophylactic or therapeutic agent for arteriosclerosis by having a selective ACAT2-inhibiting ability and exhibiting a high activity without decomposition by metabolizing enzymes.
  • the present inventors found that certain novel pyripyropene derivatives are not susceptible to hydrolysis with a metabolizing enzyme and have an extremely high inhibitory activity against ACAT2, which has drawn attention as a target of a drug for prevention and treatment of arteriosclerosis, and they thereby accomplished the present invention.
  • the present invention is a compound having the following general formula (IV) or a pharmaceutically acceptable salt, solvate, or hydrate thereof: Wherein R 1 and R 5 are respectively:
  • the present description relates to a reference compound of the general following formula (I) or a pharmaceutically acceptable salt, solvate, or hydrate thereof:
  • R 1 and R 5 are respectively:
  • the aliphatic acyloxy group is preferably a lower alkyl carbonyloxy group.
  • the term "lower alkyl” used herein means a straight- or branched-chain alkyl group having 1 to 6 carbon atoms and preferably 1 to 4 carbon atoms.
  • the term “lower alkoxy” means a straight- or branched-chain alkoxy group having 1 to 6 carbon atoms and preferably 1 to 4 carbon atoms.
  • Examples of a "lower alkylcarbonyloxy” include acetoxy, n-propionyloxy, i-propionyloxy, n-butyryloxy, i-butyryloxy, s-butyryloxy, t-butyryloxy, n-valeryloxy, neovaleryloxy, i-valeryloxy, t-valeryloxy, n-caproyloxy, and i-caproyloxy.
  • a hydrogen atom on the lower alkylcarbonyloxy may be substituted by a substituent.
  • the substituent include a halogen (F, Cl, Br or I), nitro, cyano, an amino group (including a mono- and di-(lower alkyl)amino), and a lower alkoxy.
  • alicyclic acyloxy group means a cycloalkylcarbonyloxy group having 4 - 7 ring carbon atoms. Specific examples include cyclopentylcarbonyloxy and cyclohexylcarbonyloxy. A hydrogen atom on the carbocyclic ring may be substituted by a substituent as exemplified above.
  • aromatic acyloxy group means an arylcarbonyloxy group.
  • aryl include phenyl and naphthyl groups. Therefore, examples of the aromatic acyloxy group include benzoyloxy and naphthoyloxy groups.
  • arylmethylcarbamoyl means a group of the formula -CONH-CH 2 -aryl wherein the aryl group may be a substituted aryl such as a substituted phenyl.
  • Aryl may be a substituted aryl group having one or more substituents on the aromatic ring.
  • substituents on an aromatic ring include a lower alkyl, a lower alkoxy, a halogen (F, Cl, Br or I), nitro, cyano, and an amino group (including a mono- and di-(lower alkyl)amino).
  • a substituted aryl for R 5 include o-methylphenyl, p-methoxyphenyl, o,o-dimethylphenyl, and o-fluorophenyl.
  • Examples of a substituted aryl in an arylcarbonyloxy having a substituted aryl include p-cyanophenyl, p-nitrophenyl, and p-fluorophenyl.
  • An example of a substituted aryl in an arylmethylcarbamoyl having a substituted aryl includes o,o-dimethoxyphenyl.
  • Pyripyropene derivatives according to the present invention are novel compounds which can be easily prepared, and they can selectively inhibit ACAT2 with their inhibitory activity being sustained in the living body due to their lack of susceptibility to hydrolysis by metabolizing enzymes. Therefore, these compounds are useful as drugs which are effective for prevention or treatment of arteriosclerosis.
  • a reference compound of the above Formula (II) in which R 1 is an arylcarbamoyloxy group (e.g, benzoyloxy), R 4 is acetoxy, and R 3 is benzoyloxy can be prepared in accordance with the following scheme.
  • R*CO 2 H indicates the aromatic carboxylic acid such as benzoic acid which corresponds to the arylcarbonyloxy group R 1 .
  • Compound (a) in the above scheme can be prepared in a conventional manner (see Obata et al., J. Antibiot., Vol. 49, pp. 1133-1148, 1996 , for example).
  • the conversion of compound (a) into compound (b) can be carried out in the following manner.
  • Compound (a) is reacted with 1.2 equivalents of di-tert-butylsilyl-ditrifluoromethane sulfonate or di-tert-butylsilyl dichloride in the presence of 2.4 equivalents or more of an organic amine (preferably 2,6-lutidine) in dimethylformamide (solvent) for 1 h with ice cooling.
  • the reaction mixture is subjected to conventional post-treatment to obtain compound (b).
  • the conversion of compound (b) into compound (c) can be carried out in the following manner.
  • Compound (b) is reacted for from 30 min to 2 days at room temperature in a solvent such as dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile or a mixture of these in the presence of 1 equivalent or more of the corresponding carboxylic acid R*CO 2 H, 1 equivalent or more of a condensation agent (preferably 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride or dicyclohexylcarbodiimide), and 0.5 equivalents or more of an organic base (preferably N,N-dimethylaminopyridine).
  • a condensation agent preferably 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride or dicyclohexylcarbodiimide
  • an organic base preferably N,N-dimethylaminopyridine
  • the conversion of compound (c) into compound (d) can be carried out in the following manner.
  • Compound (c) is reacted for 3 - 5 h at room temperature in a solvent such as an alcohol (preferably methanol or ethanol) or tetrahydrofuran or acetonitrile or a mixture of these in the presence of 10 equivalents or more of ammonium fluoride.
  • a solvent such as an alcohol (preferably methanol or ethanol) or tetrahydrofuran or acetonitrile or a mixture of these in the presence of 10 equivalents or more of ammonium fluoride.
  • the reaction mixture is subjected to conventional post-treatment to give compound (d) as a primary product.
  • the conversion of compound (d) into compound (e) can be carried out in the following manner.
  • Compound (d) is reacted for from 30 min to 2 days at 0° C or room temperature in a solvent such as dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile or a mixture of these in the presence of 1 equivalent or more of acetic anhydride, 1,5 equivalents or more of an organic amine (preferably triethylamine or diisopropylethylamine), and 0.5 equivalents or more of an organic base (preferably dimethylaminopyridine).
  • a solvent such as dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile or a mixture of these in the presence of 1 equivalent or more of acetic anhydride, 1,5 equivalents or more of an organic amine (preferably triethylamine or diisopropylethylamine), and 0.5 equivalents or more of an organic base (preferably dimethylamin
  • R 4 is depicted as acetoxy, but any acyloxy group other than acetoxy can be introduced as R 4 by replacing acetic anhydride by the corresponding acid anhydride when compound (d) is converted into compound (e).
  • the conversion of compound (e) into compound (f) can be carried out in the following manner.
  • Compound (e) is reacted for 1 h at room temperature in a solvent such as tetrahydrofuran, an alcohol (preferably methanol or ethanol) or acetonitrile or a mixture of these in the presence of 1 equivalent or more of a fluorine reagent (preferably triethylamine trihydrofluoride or tetrabutylammonium fluoride).
  • a fluorine reagent preferably triethylamine trihydrofluoride or tetrabutylammonium fluoride.
  • the conversion of compound (f) into compound (g) can be carried out in the following manner.
  • Compound (f) is reacted for from 30 min to 2 days at room temperature in a solvent such as dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile or a mixture of these in the presence of 1 equivalent or more of benzoic acid, 1 equivalent or more of a condensation agent (preferably 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride or dicyclohexylcarbodiimide), and 0.5 equivalents or more of an organic base (preferably dimethylaminopyridine).
  • a condensation agent preferably 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride or dicyclohexylcarbodiimide
  • an organic base preferably dimethylaminopyridine
  • R 3 is depicted as benzoyloxy, but any arylcarbonyloxy group other than benzoyloxy can be introduced as R 3 by replacing benzoic acid by the corresponding aryl carboxylic acid (e.g., a substituted benzoic acid) when compound (f) is converted into compound (g).
  • aryl carboxylic acid e.g., a substituted benzoic acid
  • R 3 is an aliphatic acyloxy group, e.g., a lower alkylcarbonyloxy group such as acetoxy or an alicyclic acyloxy group, e.g., a cycloalkylcarbonyloxy group by using an aliphatic or alicyclic carboxylic acid (e.g., acetic acid or cyclohexylcarboxylic acid) in place of benzoic acid.
  • an aliphatic or alicyclic carboxylic acid e.g., acetic acid or cyclohexylcarboxylic acid
  • a reference compound of the above Formula (III) in which R 6 is 2,4-dimethoxybenzylamino and R 3 is acetoxy can be prepared in accordance with the following scheme starting from compound (d) shown in the above scheme.
  • the conversion of compound (d) into compound (h) can be carried out in the following manner.
  • Compound (d) is reacted for 12 h at room temperature in anhydrous acetone solvent (preferably containing 5% water) in the presence of 2 equivalents or more of Jones reagent.
  • the reaction mixture is subjected to conventional post-treatment to give compound (h).
  • the conversion of compound (i) into compound (j) can be carried out in the following manner.
  • Compound (i) is reacted for from 30 min to 2 days at room temperature in a solvent such as dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile or a mixture of these in the presence of 1 equivalent or more of the corresponding amine, 1 equivalent or more of a condensation agent (preferably benzotriazol-1-yloxy-tris-dimethylaminophosphonium hexafluorophosphate/BPO), and 0.5 equivalents or more of an organic base (preferably dimethylaminopyridine).
  • a condensation agent preferably benzotriazol-1-yloxy-tris-dimethylaminophosphonium hexafluorophosphate/BPO
  • an organic base preferably dimethylaminopyridine
  • R 6 is depicted as 2,4-dimethoxybenzylamino, but a benzylamino group having a different substituent or substituents on the phenyl ring (e.g., dimethyl-, monomethyl-, or monomethoxy-substituted benzylamino group) can be introduced as R 6 by using the corresponding amine when compound (i) is converted into compound (j).
  • a benzylamino group having a different substituent or substituents on the phenyl ring e.g., dimethyl-, monomethyl-, or monomethoxy-substituted benzylamino group
  • R 3 is depicted as acetoxy, but an acyloxy group other than acetoxy can be introduced as R 3 by replacing acetic anhydride by the corresponding acid anhydride when compound (k) is converted into compound (1).
  • a compound of the above Formula (IV) in which R 5 is phenyl can be prepared in accordance with the following scheme.
  • R*CO 2 H indicates the carboxylic acid corresponding to R 1 .
  • Compound (m) in the above scheme can be prepared in a conventional manner (see Obata et al., J. Antibiot., Vol. 49, pp. 1149-1156, 1996 , for example).
  • a compound of the above Formula (IV) in which R 1 is a group of the formula -O-CH(R 7 )-R 8 where R 7 is methoxy and R 8 is p-methoxyphenyl and R 5 is phenyl can be prepared in accordance with the following scheme.
  • Compound (m) in the above scheme can be prepared in a conventional manner (see Obata et al., J. Antibiot., Vol. 49, pp. 1149-1156, 1996 , for example).
  • the conversion of compound (m) into compound (o) can be carried out in the following manner.
  • Compound (m) is reacted for 12 h at room temperature in a dimethylformamide solvent in the presence of 10 equivalents or more of p-methoxybenzaldehyde dimethylacetal and a catalytic amount of an organic acid (preferably pyridinium p-toluenesulfonate).
  • the reaction mixture is subjected to conventional post-treatment to give compound (o).
  • R 8 is depicted as p-methoxyphenyl, but an aryl group other than p-methoxyphenyl can be introduced as R 8 by using the corresponding aldehyde dimethylacetal when compound (m) is converted into compound (o).
  • a compound according to the present invention has a high inhibitory activity against ACAT2. Therefore, a compound according to the present invention can be used for prevention and treatment of arteriosclerosis in animals including human beings.
  • the present invention also provides an ACAT2 inhibitor comprising as an active ingredient the above-described compound or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a pharmaceutical composition for ACAT2 inhibition comprising the above-described compound or a pharmaceutically acceptable salt, solvate, or hydrate thereof and a pharmaceutically acceptable carrier.
  • composition according to the present invention can be formulated by any method known to those skilled in the art.
  • a compound according to the present invention may be combined with a pharmaceutically acceptable carrier such as one or more ingredients selected from sterilized water, physiological saline, vegetable oils, emulsifiers, suspending agents, surfactants, stabilizers, flavors, excipients, vehicles, preservatives, binders, and the like and mixed to form a composition in a unit dosage form which is required for generally accepted pharmaceutical practice.
  • a pharmaceutically acceptable carrier such as one or more ingredients selected from sterilized water, physiological saline, vegetable oils, emulsifiers, suspending agents, surfactants, stabilizers, flavors, excipients, vehicles, preservatives, binders, and the like and mixed to form a composition in a unit dosage form which is required for generally accepted pharmaceutical practice.
  • a compound according to the present invention or its salt can be formulated in the form of a tablet, pill, sugar-coated tablet, capsule, liquid, gel, syrup, slurry, suspension, powder, or the like by mixing it with a pharmaceutically acceptable carrier which is well known in the art.
  • any carrier which has heretofore been known in the art can be widely used.
  • a carrier include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silica; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatine solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, and polyvinylpyrrolidone; disintegrating agents such as dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, and lactose; disintegration suppressors such as sucrose, stearin cacao butter, and hydrogenated oils; absorbefacients such as quaternary ammonium salts and sodium lauryl sulf
  • a compound according to the present invention or its salt can be formulated in accordance with a conventional formulating practice using a pharmaceutically acceptable vehicle which is well known in the art as a carrier.
  • a pharmaceutically acceptable vehicle which is well known in the art as a carrier.
  • a water-soluble vehicle for use in injections include physiological saline and isotonic solutions containing glucose or other adjuvant such as D-sorbitol, D-mannose, D-mannitol, or sodium chloride. They may be used along with a suitable solubilizer, for example, an alcohol such as ethanol, a polyhydric alcohol such as propylene glycol or polyethylene glycol, or a nonionic surfactant such as polysolvate 80TM or HCO-50.
  • An oily vehicle includes sesame oil and soybean oil, and it may be used along with a solubilizer such as benzyl benzoate or benzyl alcohol.
  • a buffer such as a phosphate buffer solution or a sodium acetate buffer solution, a soothing agent such as procaine hydrochloride, a stabilizer such as benzyl alcohol or phenol, and an antioxidant may be added.
  • An injection which was prepared is usually packaged in appropriate ampoules.
  • An appropriate route of administration of a pharmaceutical composition according to the present invention includes but is not limited to oral, intrarectal, mucosal, or intraintestinal administration and intramuscular, subcutaneous, intramedullary, intrathecal, direct intraventricular, intravenous, intravitreous, intraperitoneal, intranasal, or intraocular injection.
  • the route of administration can be appropriately selected depending on the patient's age, condition, and other medicines which are also administered to the patient.
  • the dose of a pharmaceutical composition according to the present invention in each administration can be selected in the range from 0.001 mg to 10 mg per kg of body weight. Alternatively, the dose in each administration can be selected in the range from 0.1 mg to 100 mg. The dose is not necessarily limited to these ranges. Administration can be carried out once or multiple times a day, or it may be carried out once in a plurality of days.
  • the dose and dosage regimen can be suitably selected by the accompanying medical practitioner in view of the body weight, age, and condition of a patient, and other medicines which are also administered to the patient.
  • a compound according to the present invention has an improved ACAT2-inhibiting activity and is useful as a therapeutic or prophylactic agent for obesity, adiposis, hyperlipidemia, hypercholesterolemia, disorder of lipid metabolism, arteriosclerosis, or hypertension.
  • a pharmaceutical composition containing a compound according to the present invention or its pharmacologically acceptable salt, its pharmacologically acceptable ester, or other pharmacologically acceptable derivative thereof as an active ingredient is useful as a prophylactic or therapeutic drug for diseases relating to arteriosclerosis.
  • the resulting residue was purified by neutral flash silica gel column chromatography (1x4, MeOH in CH 2 Cl 2 0.5 - 1.5%), and the fractions containing the product were concentrated.
  • the resulting residue was dissolved in THF (0.5 mL), and after addition of TBAF (100 ⁇ L, 1.0 M solution in THF, 0.100 mmol) and AcOH (5.7 ⁇ L, 0.100 mmol), the mixture was stirred for 30 min at room temperature.
  • the reaction mixture was concentrated in vacuo, and the resulting residue was purified by neutral flash silica gel column chromatography (1x5, MeOH in CH 2 Cl 2 2 - 4%), and the fractions containing the product were concentrated.
  • the resulting residue was dissolved in THF (0.5 mL), and after addition of Et 3 N ⁇ 3HF (6.6 mL, 40.2 mmol), the mixture was stirred for 30 min at room temperature.
  • the resulting residue was dissolved in CH 2 Cl 2 (0.5 mL), and Ac 2 O (2.4 ⁇ L, 25.4 ⁇ mol), Et 3 N (7.1 ⁇ L, 51.0 ⁇ mol), and a catalytic amount of DMAP were added to the solution and stirred for 0.5 h at room temperature.
  • the resulting residue was roughly purified by neutral flash silica gel column chromatography (1x4, MeOH in CH 2 Cl 2 0 - 1.5%), and the fractions containing the product were concentrated.
  • the resulting residue was dissolved in THF (0.5 mL), and after addition of Et 3 N ⁇ 3HF (18.0 ⁇ L, 113 ⁇ mol), the mixture was stirred for 30 min at room temperature.
  • the reaction mixture was concentrated in vacuo, and the resulting residue was roughly purified by neutral flash silica gel column chromatography (1x5+1, MeOH in CH 2 Cl 2 3 - 10%), and the fractions containing the product were concentrated.
  • the resulting residue was roughly purified by neutral flash silica gel column chromatography (1x15, MeOH in CH 2 Cl 2 0 - 1.5%), and the fractions containing the product were concentrated.
  • the resulting residue was dissolved in THF (1.0 mL), and after addition of Et 3 N ⁇ 3HF (39.0 ⁇ L, 241 ⁇ mol), the mixture was stirred for 30 min at room temperature.
  • the reaction mixture was concentrated in vacuo, and the resulting residue was roughly purified by neutral flash silica gel column chromatography (1x5+1, MeOH in CH 2 Cl 2 3 - 10%), and the fractions containing the product were concentrated.
  • n-hexanoic anhydride (23.6 ⁇ L, 102. ⁇ mol), Et 3 N (28.5 ⁇ L, 205 ⁇ mol), and a catalytic amount of DMAP were added to a solution of r (20.0 mg, 34.1 mmol) in CH 2 Cl 2 (0.5 mL) at 0° C and stirred for 3 h at room temperature.
  • MeOH was added to the reaction mixture to terminate the reaction, and EtOAc was then added.
  • the organic layer was washed with water and dried over anhydrous sodium sulfate.
  • the solution was filtered, and the filtrate was dried over anhydrous sodium sulfate and concentrated in vacuo.
  • the resulting residue was dissolved in THF (0.6 mL), and after addition of Et 3 N ⁇ 3HF (11.1 ⁇ L, 68.3 ⁇ mol), the mixture was stirred for 30 min at room temperature.
  • the reaction mixture was concentrated in vacuo, the resulting residue was roughly purified by neutral flash silica gel column chromatography (1x4, MeOH in CH 2 Cl 2 0 - 3%), and the fractions containing the product were concentrated.
  • the resulting residue was dissolved in CH 2 Cl 2 (0.5 mL), and Ac 2 O (4.6 ⁇ L, 48.5 ⁇ mol), Et 3 N (7.4 ⁇ L, 52.8 ⁇ mol), and a catalytic amount of DMAP were added to the solution and stirred for 1 h at room temperature.
  • ESI-LRMS m/z 610 (M+Na + ); ESI-HRMS (TFA-Na) calcd. for C 34 H 37 NaNO 8 610.2417 (M+Na+), found 610.2405 (M+Na + ).
  • o-anisaldehyde (73.6 ⁇ L, 0.607 mmol) and a catalytic amount of PPTS were added to a solution of a (18.5 mg, 40.3 ⁇ mol) in DMF (1.0 mL) and stirred for 24 h at room temperature.
  • the reaction mixture was diluted with EtOAc, and the organic layer was washed with water and dried over anhydrous sodium sulfate.
  • the solution was filtered, and the filtrate was concentrated in vacuo.
  • the resulting residue was purified by neutral flash silica gel column chromatography (1x3, MeOH in CH 2 Cl 2 0 - 5%), and the fractions containing the product were concentrated.
  • o-anisaldehyde (59.7 ⁇ L, 0.492 mmol) and a catalytic amount of PPTS were added to a solution of a (15.0 mg, 32.7 ⁇ mol) in DMF (0.5 mL) and stirred for 24 h at room temperature.
  • the reaction mixture was diluted with EtOAc, and the organic layer was washed with water and dried over anhydrous sodium sulfate.
  • the solution was filtered, and the filtrate was concentrated in vacuo.
  • the resulting residue was purified by neutral flash silica gel column chromatography (1x3, MeOH in CH 2 Cl 2 0 - 5%), and the fractions containing the product were concentrated.
  • o-fluorobenzaldehyde 85.5 ⁇ L, 0.820 mmol
  • a catalytic amount of PPTS were added to a solution of a (25.0 mg, 54.5 ⁇ mol) in DMF (1.0 mL) and stirred for 24 h at room temperature.
  • the reaction mixture was diluted with EtOAc, and the organic layer was washed with water and dried over anhydrous sodium sulfate.
  • the solution was filtered, and the filtrate was concentrated in vacuo.
  • the resulting residue was purified by neutral flash silica gel column chromatography (1x3, MeOH in CH 2 Cl 2 0 - 5%), and the fractions containing the product were concentrated.
  • o-fluorobenzaldehyde 85.5 ⁇ L, 0.820 mmol
  • a catalytic amount of PPTS were added to a solution of a (25.0 mg, 54.5 ⁇ mol) in DMF (1.0 mL) and stirred for 24 h at room temperature.
  • the reaction mixture was diluted with EtOAc, and the organic layer was washed with water and dried over anhydrous sodium sulfate.
  • the solution was filtered, and the filtrate was concentrated in vacuo.
  • the resulting residue was purified by neutral flash silica gel column chromatography (1x3, MeOH in CH 2 Cl 2 0 - 5%), and the fractions containing the product were concentrated.
  • a test of stability of pyripyropene derivatives against metabolizing enzymes in the liver was carried out by the method of Ishigami et al. (Drug Meta. Dispos., Vol. 30, pp. 904-910, 2002 ).
  • the enzyme source which was used was a hepatic microsome prepared from female SD rats (XenoTech).
  • the analysis was conducted using a ultra high performance liquid chromatography (system: Shimadzu Prominence, column: Shim Pack XR-ODS, 2.0 ⁇ x 75 mm, 40° C, Shimadzu Corporation). Elution was carried out with a linear concentration gradient starting with an aqueous 0.1% phosphoric acid solution containing 5% acetonitrile and terminating after 6 min with an aqueous 0.1% phosphoric acid solution containing 95% acetonitrile while detection was conducted at a wavelength of 320 nm.
  • the peak area of each pyripyropene derivative was calculated using analytic software (LCMS solution, Shimadzu Corporationi), and the amount of the pyripyropene derivative remaining after each reaction period was calculated taking the peak area of the pyripyropene derivative immediately before the commencement of reaction as 100%.
  • PRD 007, PRD 009, PRD 021, PRD 024, PRD 025, PRD 026, PRD 043, and PRD 056 are the compounds having the following formulas.
  • An enzyme source was prepared according to the method of Uelmen et al. (J. Biol. Chem., Vol. 270, pp. 26192-26201, 1995 ) which was partly modified.
  • the enzyme source which was used was a membrane fraction derived from murine hepatic microsome.
  • Mouse livers were homogenized in buffer solution A (50 mM Tris HCl solution (pH 7.8), 1 mM ethylene diamine tetraacetate, and 1 mM phenylmethanesulfonyl fluoride) using a Potter-type homogenizer (Tokyo-Riko).
  • the homogenate was centrifuged at 12000 x g, and the supernatant was subjected to ultracentrifugation at 100000 x g.
  • the resulting sediment was collected as a microsome fraction, and this fraction was adjusted so as to have a protein concentration of 5 mg/mL using buffer solution A.
  • the above-described enzyme source 200 ⁇ g as protein
  • 200 mM bovine serum albumin 200 mM bovine serum albumin
  • [1- 14 C] oleoyl coenzyme A final concentration 170 ⁇ M, 0.090 ⁇ Ci
  • the particular pyripyropene derivative to be tested 10 ⁇ L of a methanol solution with a concentration of 1, 0.1, 0.01, 0.001, 0.0001, or 0.00001 mg/mL
  • buffer solution A so as to give a total volume of 200 ⁇ L
  • the mixture was allowed to react for 5 min at 37° C.
  • 10 ⁇ L of methanol were used in place of the pyripyropene derivative.
  • the concentration at which 50% inhibition of the enzyme activity was achieved (IC 50 ) was calculated.
  • the compounds according to the present invention exhibit an extremely high inhibitory activity against ACAT 2.
  • a novel compound according to the present invention not only exhibits a higher inhibitory activity against ACAT2 but has a longer half-life against metabolism by hepatic enzymes, or it is less metabolizable in the liver, so its high inhibitory activity lasts longer. Accordingly, a novel compound according to the present invention is expected to be useful as a specific ACAT2 inhibitor of high activity and prolonged action in the treatment of arteriosclerosis.
  • a method for testing the ACAT2-inhibiting activity is not limited to the above-described method.
  • a microsome prepared by the small intestine or liver of an animal such as a rat or monkey may be used as a source of ACAT2 enzyme.
  • cultured cells such as Caco-2 intestinal cells, primarily cultured hepatic cells, or HepG2 hepatic cells
  • a microsome prepared from cultured cells having highly expressed ACAT2 can be used as a source of ACAT2 enzyme.

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Claims (5)

  1. Verbindung, die die folgende allgemeine Formel (IV) hat, oder ein pharmazeutisch akzeptables Salz, Solvat oder Hydrat derselben:
    Figure imgb0061
     wobei R1 und R5 entsprechend sind:
    4-Cyanobenzoyloxy und 4-(N,N-Dimethylamino)-phenyl;
    4-Cyanobenzoyloxy und 2-Methylphenyl;
    4-Cyanobenzoyloxy und 4-Methylphenyl;
    4-Fluorobenzoyloxy und 2-Methylphenyl;
    4-Fluorobenzoyloxy und 4-Methylphenyl;
    4-Cyanobenzoyloxy und 3-Methylphenyl;
    4-Fluorobenzoyloxy und 3-Methylphenyl;
    4-Cyanobenzoyloxy und 2,4-Dimethylphenyl;
    4-Fluorobenzoyloxy und 2,4-Dimethylphenyl;
    4-Cyanobenzoyloxy und 2-Methoxyphenyl;
    4-Fluorobenzoyloxy und 2-Methoxyphenyl;
    4-Cyanobenzoyloxy und 2-Fluorophenyl;
    4-Fluorobenzoyloxy und 2-Fluorophenyl oder
    4-Cyanobenzoyloxy und 2,6-Dimethylphenyl.
  2. Verbindung nach Anspruch 1, wobei R1 4-Cyanobenzoyloxy und R5 2-Methylphenyl ist.
  3. Pharmazeutische Zusammensetzung für ACAT2-Hemmung, die die Verbindung nach Anspruch 1 oder 2 oder ein pharmazeutisch akzeptables Salz, Solvat oder Hydrat derselben oder einen pharmazeutisch akzeptablen Träger umfasst.
  4. Verbindung nach Anspruch 1 oder 2 oder ein pharmazeutisch akzeptables Salz, Solvat oder Hydrat derselben zur Verwendung in der Therapie bei einem Verfahren zur Verhinderung oder Behandlung von Krankheiten, die mit ACAT2 verbunden sind.
  5. Verbindung nach Anspruch 4 zur Verwendung bei der Therapie in einem Verfahren zur Verhinderung oder Behandlung von Arteriosklerose.
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